TTK defines a high-risk Oral Squamous Cell Carcinoma subtype through dual mTORC1/NF-?B activation

Oral squamous cell carcinoma (OSCC) remains challenging to treat due to significant tumor heterogeneity, highlighting the need for identifying molecular subtypes with distinct therapeutic vulnerabilities. Here, we present a comprehensive molecular analysis of 709 OSCC cases, integrating single-cell RNA sequencing and bulk transcriptomic data. We identify a distinct molecular subtype of OSCC characterized by co-activation of the mTORC1 and NF-?B pathways, with TTK emerging as a central regulator of this co-activation. This subtype exhibits heightened genomic instability. Using protein mass spectrometry and immunoprecipitation, we demonstrate that TTK activates the NF-?B pathway through interaction with the TAK1-TAB protein complex. Functional in vitro and in vivo experiments further reveal that TTK inhibition significantly enhances cisplatin sensitivity in OSCC. These findings provide a basis for patient stratification and underscore the potential of targeting TTK in therapeutic strategies for this high-risk OSCC subtype. Overall design: RNA-seq profiling of wildtype SCC-15 and CAL-27 cells and their knockdown derivatives (shTTK).